We wish to characterize the mechanisms for responsible for focal segmental glomerulosclerosis (FSGS) and use these findings to devise more effective therapy. First, we have investigated the pathogenesis of HIV-associated FSGS. We have studied a mouse transgenic for two HIV accessory proteins, Tat and Vpr, and have found that this mouse develops FSGS. Since Tat mice do not develop kidney disease, we believe that Vpr may be the nephrotoxic protein. Vpr is highly toxic to developing mouse embryos. Therefore, we have recently established transgenic lines which will express Vpr under the control of a tetracycline inducible promoter. We have also established transgenic lines which will express Vpr mutated to eliminate cell cycle arrest function. Second, we are studying the genetics of FSGS in human patients. We have collected blood and prepared immortalized B cell lines as a source of DNA from 200 African-American patients with FSGS and a control group 215 African Americans infected with HIV but without renal disease. We have initiated candidate gene analysis and have identified significant differences in the ACE and TGF-beta genes between the two groups. Third, we have investigated the possibility that other viruses besides HIV-1 contribute to the pathogenesis of FSGS. We have identified infectious SV40 in the urinary cells of 40% of FSGS patients, 15% of other glomerular disease patients, and 5% of healthy volunteers. These data suggest that either SV40 infections may be relatively common in the healthy population, remain latent in kidney, and are activated by kidney disease, or alternatively that SV40 may play a role in the pathogenesis of kidney disease, including possibly FSGS. Fourth, we have initiated two treatment studies of idiopathic FSGS, using a pilot study design. We are treating patients with newly-diagnosed FSGS with intermittent dexamethasone therapy, and we are treating patients with steroid-resistant FSGS with the anti-fibrotic agent pirfenidone.